Treatment with opioid receptor-antagonist naloxegol significantly improved opioid-associated constipation, compared with placebo, without affecting pain scores or daily opioid requirements, according to data from two identical double-blind studies.
Outpatients with noncancer pain who were given 25 mg of naloxegol showed a significantly shorter time to first spontaneous bowel movement after treatment, compared with those given placebo – a median time of 5.9 hours and 12 hours in the two studies, compared with 35.8 hours and 37.2 hours with placebo, according to a study published online June 4 in the New England Journal of Medicine.
Treatment with naloxegol was also associated with a significantly greater number of spontaneous bowel movements over the course of the 12-week study period, compared with placebo, and an increase in the mean number of days per week with one or more spontaneous bowel movements.
The Food and Drug Administration is currently considering whether to approve naloxegol; the agency is expected to decide by Sept. 16, 2014.
The two phase III randomized, controlled studies were nearly identical in size – one including 652 individuals with opioid-induced constipation, and the other including 700 – and entirely identical in design: Participants were randomized to receive either 25 mg or 12.5 mg of naloxegol daily, or placebo.
"In both studies, naloxegol at a dose of 25 mg was associated with an increased rate of response (10-15 percentage points higher than the response with placebo) over a period of 12 weeks," wrote Dr. William D. Chey of the University of Michigan Health System, Ann Arbor, and his colleagues.
The higher dose of naloxegol also was associated with more significant improvements in severity of straining, stool consistency, and the frequency of days with complete, spontaneous bowel movements.
Naloxegol’s benefits were even greater among individuals who had previously failed to respond to laxatives before study enrollment, which accounted for 71% of participants, a prespecified subgroup analysis showed (N. Engl. J. Med. 2014 June 4 [doi:10.1056/NEJMoa1310246]).
"In clinical practice, osmotic and stimulant laxatives are likely to be used before more expensive prescription medications," the researchers wrote. "Thus, the finding that naloxegol proved beneficial in patients who had persistent symptoms of opioid-induced constipation despite using standard laxatives is of potential importance."
There were some dose-related side effects observed in the naloxegol group, including abdominal pain, nausea, diarrhea, and vomiting, occurring soon after initiation of treatment. But most of these effects were mild to moderate.
There had been concern about potential cardiovascular side effects, which had been observed previously with alvimopan, another peripherally-acting mu-opioid antagonist. However the incidence of major cardiovascular events was rare and similar across both active and placebo groups.
Researchers found no significant interaction between naloxegol treatment and daily opioid dose, and there also were no significant differences in the mean change from baseline in pain scores.
Around half of the patients enrolled were taking opioids for back pain, while other reasons included arthritis, joint pain, or fibromyalgia. On average, participants had been taking opioids for 3.65 years.
AstraZeneca supported the study, and the authors declared a range of grants, consultancies, and other financial relationships with several pharmaceutical companies, including AstraZeneca.